Quinazoline derivatives and preparation method and application thereof

A technology of quinazoline and derivatives, which is applied in the field of quinazoline derivatives and can solve problems such as side reactions

Inactive Publication Date: 2011-08-10
SHANGHAI ALLIST PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The quinazoline EGFR inhibitors reported so far are all ATP competitive inhibitors of w

Method used

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  • Quinazoline derivatives and preparation method and application thereof
  • Quinazoline derivatives and preparation method and application thereof
  • Quinazoline derivatives and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] N-[4-(3-chloro-4-hydroxy-phenylamino)-7-methoxy-quinazolin-6-yl-]-crotonamide

[0050]

[0051] In a flask equipped with a condensing device, the raw material (Ia-1) 4-hydroxy-3-chloroaniline 1.37 g (5.6 mmol) and (Ib-1) 6-nitro-7-methoxy-4- 1.20g (5.7mmol) of chloro-quinazoline was dissolved in 80ml of isopropanol and reacted under reflux for 3h. A large amount of yellow solid precipitated in the system, filtered, and washed with saturated sodium bicarbonate aqueous solution to pH=8. The sample was dried in vacuum, and the compound was identified as (Ic-1).

[0052] Add 1.60g (3.77mmol) of the above (Ic-1) compound, 1.05g (18.85mmol, 5eq) of reduced iron powder, 2ml of glacial acetic acid, 40ml of methanol, and reflux under an oil bath at 85℃ into a flask equipped with reflux condenser After 2.5 hours of reaction, the iron powder was removed by filtration, the filtrate was diluted with ethyl acetate, washed with sodium bicarbonate solution, washed with water, and the organ...

Embodiment 2

[0058] N-[4-(3-Chloro-4-hydroxy-phenylamino)-quinazolin-6-yl-]-crotonamide

[0059]

[0060] In a flask equipped with a condenser, the raw materials (Ia-1) 4-hydroxy-3-chloroaniline 1.37 g (5.6 mmol) and (Ib-2) 6-nitro-4-chloro-quinazoline 1.20 g (5.7 mmol) was dissolved in 80ml of isopropanol and reacted under reflux for 3h. A large amount of yellow solid precipitated in the system, filtered, and the solid was washed with saturated sodium bicarbonate aqueous solution to pH=8. The sample was dried in vacuum, and the compound was identified as (Ic-2).

[0061] Add 1.60g (3.77mmol) of the above (Ic-2) compound, 1.05g (18.85mmol, 5eq) of reduced iron powder, 2ml of glacial acetic acid, 40ml of methanol, and reflux under an oil bath at 85°C into a flask equipped with a reflux condenser After 2.5 hours of reaction, the iron powder was removed by filtration, the filtrate was diluted with ethyl acetate, washed with sodium bicarbonate solution, washed with water, and the organic phase was...

Embodiment 3

[0067] N-[4-(3-Chloro-4-hydroxy-phenylamino)-quinazolin-6-yl-]-acrylamide

[0068]

[0069] In a 100ml flask, add 1.2g (3.04mmol) of the (Id-2) compound of Example 2 above, 0.8ml (6.1mmol, 2eq) of triethylamine, 1.02ml (12.1mmol, 4eq) of acryloyl chloride under ice bath ), THF40ml, gradually warmed to room temperature for reaction. After 3h, the reaction was stopped, filtered, the solid was washed with water to neutrality, and dried to obtain 1.1g of solid. The compound was identified as (3) with a yield of 68%.

[0070] H 1 -NMR (400MHz, CDCl 3 +DMSO):

[0071] δ8.63(s, 1H), 8.53(s, 1H), 8.14(s, 3H), 7.71-7.64(dd, 2H), 7.23(s, 1H), 7.06-7.02(m, 2H), 6.78- 6.76(d, 1H), 5.92-5.89(d, 1H), 5.54-5.48(m, 1H)

[0072] ESI(+): 341

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PUM

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Abstract

The invention discloses quinazoline derivatives serving as irreversible tyrosine kinase inhibitors, and use of the derivatives as inhibitors for human epidermal growth factor receptor (EGFR) mutant T790M and anticancer agents. The invention also relates to a preparation method for the quinazoline derivatives, and a medicinal composition containing the quinazoline derivatives.

Description

Technical field [0001] The present invention relates to a class of quinazoline derivatives as tyrosine kinase inhibitors, and the application of these derivatives as inhibitors of epidermal growth factor receptor (EGFR) mutant T790M and anticancer agents. The present invention also relates to its preparation method and a pharmaceutical composition containing quinazoline derivatives. Background technique [0002] Cancer is considered a disease of the intracellular signal transduction system or signal transduction mechanism. The most common cause of cancer is a series of defects, which can be defects in protein (when it is mutated), or defects in regulation of the amount of protein in cells, resulting in overproduction or underproduction of protein. Mutations in cell surface receptors (the mutations usually transmit signals to cells through tyrosine kinases) can cause kinases to be activated in the absence of ligands and transmit signals that do not actually exist. Alternatively,...

Claims

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Application Information

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IPC IPC(8): C07D239/94A61K31/517A61P35/00
CPCC07D239/94A61K31/517A61P35/00
Inventor 姜勇郭建辉
Owner SHANGHAI ALLIST PHARM CO LTD
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